Mutational spectra analysis reveals bacterial niche and transmission routes

Abstract

As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to identify disrupted DNA repair processes and niche-specific mutagen exposure. Here we reconstructed mutational spectra for 84 clades from 31 diverse bacterial species, assigned signatures to specific DNA repair pathways using hypermutator lineages, and, by comparing mutational spectra of clades from different environmental and biological locations, extracted reproducible niche-associated mutational signatures. We show that mutational spectra can predict general and specific bacterial niches and therefore reveal the site of infection and types of transmission routes for established and emergent human bacterial pathogens.

Mutational spectra distinguish SARS-CoV-2 replication niches

“…All bacterial SBS spectra were calculated in a previous publication (Ruis 2022) from alignments of whole genome sequences. As the strand on which the original mutation occurred cannot be determined for DNA pathogens, we combine symmetrical mutations within DNA spectra (Ruis 2022). The known environmental Mycobacteria and Burkholderia clades include Mycobacterium canettii, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera , non-dominant circulating clone clades within Mycobacterium abscessus , the non-main clade of Mycobacterium kansasii and five phylogenetic groups within Burkholderia pseudomallei .…”

“…Within the lung clades, we include known lung lineages Mycobacterium tuberculosis lineages 1-7 and the epidemic clones within Burkholderia cenocepacia . We additionally include the M. abscessus dominant circulating clones (DCCs), the main cluster of M. kansasii and Mycobacterium leprae , which we previously inferred to live wholly or partially within the lung on the basis of their mutational patterns and additional epidemiological information (Ruis 2022).…”

“…All bacterial SBS spectra were calculated in a previous publication (Ruis 2022) from alignments of whole genome sequences. As the strand on which the original mutation occurred cannot be determined for DNA pathogens, we combine symmetrical mutations within DNA spectra (Ruis 2022).…”

“…Additionally, the consistent contextual patterns within G>T mutations across SARS-CoV-2 lineages ( Figure 1A ) suggests that the same mutagen is active within both the LRT and URT, but is more active within the LRT. We have previously used decomposition analysis to infer that reactive oxygen species and tobacco smoke may contribute to elevated C:G>A:T mutations in lung bacteria (Ruis 2022). Each of these mutagens predominantly exert mutagenic effects through damage of guanine nucleotides (Alexandrov 2016, Zou 2021) and therefore both could drive G>T mutations.…”

“… Abstract Exposure to different mutagens leaves distinct mutational patterns that can allow prediction of pathogen replication niches (Ruis 2022). We therefore hypothesised that analysis of SARS-CoV-2 mutational spectra might show lineage-specific differences, dependant on the dominant site(s) of replication and onwards transmission, and could therefore rapidly infer virulence of emergent variants of concern (VOC; Konings 2021).…”